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Blood Oct 2019β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the... (Review)
Review
β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the production of adult hemoglobin. Gene therapy is a potential treatment option for patients lacking an allogenic compatible hematopoietic stem cell (HSC) donor. New-generation lentiviral vectors (LVs) carrying a β-globin-like gene have revolutionized this field by allowing effective HSC transduction, with no evidence of genotoxicity to date. Several clinical trials with different types of vector are underway worldwide; the initial results are encouraging with regard to the sustained production of therapeutic hemoglobin, improved biological parameters, a lower transfusion requirement, and better quality of life. Long-term follow-up studies will confirm the safety of LV-based gene therapy. The optimization of patient conditioning, HSC harvesting, and HSC transduction has further improved the therapeutic potential of this approach. Novel LV-based strategies for reactivating endogenous fetal hemoglobin (HbF) are also promising, because elevated HbF levels can reduce the severity of both β-thalassemia and SCD. Lastly, genome-editing approaches designed to correct the disease-causing mutation or reactivate HbF are currently under investigation. Here, we discuss the clinical outcomes of current LV-based gene addition trials and the promising advantages of novel alternative therapeutic strategies.
Topics: Anemia, Sickle Cell; Animals; Clinical Trials as Topic; Fetal Hemoglobin; Gene Editing; Genetic Therapy; Genetic Vectors; Hemoglobinopathies; Humans; Lentivirus; beta-Globins; beta-Thalassemia
PubMed: 31467062
DOI: 10.1182/blood.2019000949 -
Medecine Sciences : M/S May 2016
Topics: Anemia, Sickle Cell; France; Hemoglobinopathies; History, 20th Century; History, 21st Century; Pediatricians; Research Personnel
PubMed: 27225929
DOI: 10.1051/medsci/20163205023 -
Frontiers in Immunology 2020Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow... (Review)
Review
Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow failure syndromes, and primary immunodeficiencies. Early establishment of donor-derived innate and adaptive immunity following HCT is associated with improved overall survival, lower risk of infections and decreased incidence of graft failure. Immune reconstitution (IR) is impacted by numerous clinical variables including primary disease, donor characteristics, conditioning regimen, and graft versus host disease (GVHD). Recent advancements in HCT have been directed at reducing toxicity of conditioning therapy, expanding donor availability through use of alternative donor sources, and addressing morbidity from GVHD with novel graft manipulation. These novel transplant approaches impact the kinetics of immune recovery, which influence post-transplant outcomes. Here we review immune reconstitution in pediatric patients undergoing HCT for non-malignant disorders. We explore the transplant-associated factors that influence immunologic recovery and the disease-specific associations between IR and transplant outcomes.
Topics: Age Factors; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hemoglobinopathies; Humans; Immune Reconstitution; Primary Immunodeficiency Diseases; Risk Factors; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome
PubMed: 33013851
DOI: 10.3389/fimmu.2020.01988 -
Clinical Medicine (London, England) May 2022Sickle cell disease is a common inherited disorder that is characterised by chronic haemolysis and vaso-occlusive episodes, resulting in severe pain and end-organ...
Sickle cell disease is a common inherited disorder that is characterised by chronic haemolysis and vaso-occlusive episodes, resulting in severe pain and end-organ damage. The most frequent acute manifestation of sickle cell disease is a painful vaso-occlusive crisis, which can, in some cases, develop into a sickle chest crisis: a life-threatening complication of sickle cell disease that requires early recognition and prompt intervention to prevent progressive respiratory failure. In addition to the acute complications, patients with sickle cell disease are also at risk of a number of chronic complications that require multidisciplinary specialist input.
Topics: Anemia, Sickle Cell; Humans
PubMed: 35584832
DOI: 10.7861/clinmed.2022-0143 -
Antioxidants & Redox Signaling May 2017Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates... (Review)
Review
SIGNIFICANCE
Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The β-globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected.
CRITICAL ISSUES
While HbE by itself presents as a mild anemia and a single gene for β-thalassemia is not serious, it remains unexplained why HbE/β-thalassemia (HbE/β-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/β-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess α-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events.
FUTURE DIRECTIONS
Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26, 794-813.
Topics: Animals; Hemoglobin E; Hemoglobinopathies; Humans; Oxidative Stress; Point Mutation; beta-Thalassemia
PubMed: 27650096
DOI: 10.1089/ars.2016.6806 -
Blood Cells, Molecules & Diseases Sep 2023Prior literature has established a positive association between sickle cell disease and risk of contracting SARS-CoV-2. Data from a cross-sectional study evaluating...
Prior literature has established a positive association between sickle cell disease and risk of contracting SARS-CoV-2. Data from a cross-sectional study evaluating COVID-19 testing devices (n = 10,567) was used to examine the association between underlying health conditions and SARS-CoV-2 infection in an urban metropolis in the southern United States. Firth's logistic regression was used to fit the model predicting SARS-CoV-2 positivity using vaccine status and different medical conditions commonly associated with COVID-19. Another model using the same method was built using SARS-CoV-2 positivity as the outcome and hemoglobinopathy presence, age (<16 Years vs. ≥16 Years), race/ethnicity and comorbidities, including hemoglobinopathy, as the factors. Our first model showed a significant association between hemoglobinopathy and SARS-CoV-2 infection (OR: 2.28, 95 % CI: (1.17,4.35), P = 0.016). However, in the second model, this association was not maintained (OR: 1.35, 95 % CI: (0.72,2.50), P = 0.344). We conclude that the association between SARS-CoV-2 positivity and presence of hemoglobinopathies like sickle cell disease is confounded by race, age, and comorbidity status. Our results illuminate previous findings by identifying underlying clinical/demographic factors that confound the reported association between hemoglobinopathies and SARS-CoV-2. These findings demonstrate how social determinants of health may influence disease manifestations more than genetics alone.
Topics: Humans; United States; Adolescent; SARS-CoV-2; COVID-19; COVID-19 Testing; Prevalence; Cross-Sectional Studies; Hemoglobinopathies; Anemia, Sickle Cell
PubMed: 37257234
DOI: 10.1016/j.bcmd.2023.102756 -
Cold Spring Harbor Perspectives in... Oct 2012Sickle cell disease (SCD) and β-thalassemia, two monogenic diseases caused by mutations in the β-globin gene, affect millions of individuals worldwide. These... (Review)
Review
Sickle cell disease (SCD) and β-thalassemia, two monogenic diseases caused by mutations in the β-globin gene, affect millions of individuals worldwide. These hemoglobin disorders are characterized by extreme clinical heterogeneity, complicating patient management and treatment. A better understanding of this patient-to-patient clinical variability would dramatically improve care and might also guide the development of novel therapies. Studies of the natural history of these β-hemoglobinopathies have identified fetal hemoglobin levels and concomitant α-thalassemia as important modifiers of disease severity. Several small-scale studies have attempted to identify additional genetic modifiers of SCD and β-thalassemia, without much success. Fortunately, improved knowledge of the human genome and the development of new genomic tools, such as genome-wide genotyping arrays and next-generation DNA sequencers, offer new opportunities to use genetics to better understand the causes of the many complications observed in β-hemoglobinopathy patients. Here I discuss the most important factors to consider when planning an experiment to find associations between β-hemoglobinopathy-related complications and DNA sequence variants, with a focus on how to successfully perform a genome-wide association study. I also review the literature and explain why most published findings in the field of SCD modifier genetics are likely to be false-positive reports, with the goal to draw lessons allowing investigators to design better genetic experiments.
Topics: Anemia, Sickle Cell; Fetal Hemoglobin; Genes, Modifier; Genetic Predisposition to Disease; Genome-Wide Association Study; Hemoglobinopathies; Humans; Mutation; beta-Globins; beta-Thalassemia
PubMed: 23028136
DOI: 10.1101/cshperspect.a015032 -
Archives of Gynecology and Obstetrics Nov 2021To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait.
PURPOSE
To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait.
MATERIALS AND METHODS
Retrospective cohort study was conducted to compare adverse maternal and neonatal outcomes between pregnant women with a hemoglobinopathy trait (study group; n = 172), and without a hemoglobinopathy trait (control group; n = 360). The medical data were extracted from clinical records of pregnant women attending antenatal care and delivering at the University Hospital Basel or University Hospital Zurich between 2015 and 2018.
RESULTS
A total of 172 pregnant women with a hemoglobinopathy trait and 360 controls were recruited. Apart from fetal acidosis, the groups did not differ significantly in any variables of adverse neonatal outcomes. Whereas, among the maternal outcomes the rate of abortion, gestational diabetes mellitus, bacteriuria or urinary tract infection, intrahepatic cholestasis, abnormal placentation and anemia postpartum were significantly increased in women with a hemoglobinopathy trait.
CONCLUSION
In our study, a hemoglobinopathy trait increased the risk of adverse maternal outcomes but did not increase adverse neonatal outcomes.
Topics: Acidosis; Adolescent; Adult; Bacteriuria; Case-Control Studies; Female; Hemoglobinopathies; Humans; Infant, Newborn; Middle Aged; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Retrospective Studies; Young Adult
PubMed: 33842991
DOI: 10.1007/s00404-021-06058-y -
Seminars in Perinatology Aug 2007Anemia is a commonly encountered problem in the fetal and neonatal period, and can lead to significant morbidity and mortality. Intrinsic disorders of the erythrocyte,... (Review)
Review
Anemia is a commonly encountered problem in the fetal and neonatal period, and can lead to significant morbidity and mortality. Intrinsic disorders of the erythrocyte, such as the hemoglobinopathies, enzyme deficiencies, and membrane defects are common causes of neonatal anemia. Genetic diseases that lead to decreased erythrocyte production, such as Diamond-Blackfan anemia, Schwachman-Diamond syndrome, and Congential Dyserythropoietic Anemia, are rare causes of perinatal anemia, but are important to recognize as they are often associated with other congenital abnormalities and require specialized treatment. This review focuses on the perinatal presentation and management of intrinsic erythrocyte disorders, as well as on the diagnosis and management of genetic conditions leading to erythrocyte underproduction.
Topics: Anemia; Erythrocytes; Glucosephosphate Dehydrogenase Deficiency; Hematologic Diseases; Hemoglobinopathies; Humans; Infant, Newborn; Pyruvate Kinase
PubMed: 17825683
DOI: 10.1053/j.semperi.2007.05.003 -
European Journal of Haematology Mar 2017This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies.
METHODS
Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions.
RESULTS
Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies.
CONCLUSION
Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.
Topics: Chelation Therapy; Drug Therapy, Combination; Hemoglobinopathies; Humans; Iron Chelating Agents; Iron Overload; Transfusion Reaction
PubMed: 27893170
DOI: 10.1111/ejh.12833